Compounds for the inhibition of apoptosis

Abstract

The present invention relates to compounds of formula (I) as well as to drug conjugates based on compounds of formula (I) acting as apoptosis inhibitors, as well as to processes for their preparation, to pharmaceutical compositions containing them and their use in medicine.

1 . A compound of general formula I, 
       
         
           
           
               
               
           
         
       
       its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof and the pharmaceutically acceptable solvates and addition salts thereof, wherein:
 R1 represents (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, —(CH 2 ) 1-3 —NHCO—(C 1 -C 3 )alkyl, —(CH 2 ) 1-3 —CONRaRb, —(CH 2 ) 0-3 -(3-6)Cy, —(CH 2 ) 0-3 -(5-6)Hetcy, —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), —(CH 2 ) 1-3 -(5-10)Hetar, —(CH 2 ) 2 —CH(phenyl) 2 , —(CH 2 ) 2 —CH(phenyl)[(5-6)Hetar] or —(CH 2 ) 2 —CH[(5-6)Hetar] 2 ; 
 R2 represents —(CH 2 ) 0-3 -(3-6)Cy, —(CH 2 ) 0-3 -(5-6)Hetcy, —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), —(CH 2 ) 1-3 -(5-10)Hetar, —(CH 2 ) 2 —CH(phenyl) 2 , —(CH 2 ) 2 —CH(phenyl)[(5-6)Hetar] or —(CH 2 ) 2 —CH[(5-6)Hetar] 2 ; 
 R3 represents —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), or —(CH 2 ) 1-3 -(5-6)Hetar; 
 (C 1 -C 5 )alkyl and —(C 2 -C 5 )alkenyl may be optionally substituted with one or more substituents selected from —O—(C 1 -C 2 )alkyl, —S—(C 1 -C 2 )alkyl, —NH 2 , —NH—(C 1 -C 2 )alkyl and —N[(C 1 -C 2 )alkyl] 2 ; 
 (C 1 -C 3 )alkyl can be optionally substituted with one or more halogen atoms; 
 Ra and Rb independently represent —H or —(C 1 -C 3 )alkyl 
 (3-6)Cy represents a radical of a 3- to 6-membered partially unsaturated or saturated carbocyclic ring; 
 (5-6)Hetcy represents a C- or N-radical of a 5- or 6-membered, partially unsaturated or saturated carbocyclic ring containing from one or two heteroatoms independently selected from O, S and N; 
 Cy and Hetcy can be optionally substituted with one or more substituents selected from halogen, —CF 3  and —OH; 
 (5-6)Hetar and (5-10)Hetar represent a C- or N-radical of an aromatic 5- or 6-membered and 5- to 10-membered ring respectively; containing from one to four heteroatoms independently selected from O, S and N; 
 phenyl, 1-naphthyl, 2-naphthyl, (5-6)Hetar and (5-10)Hetar may be optionally substituted with one or more substituents selected from halogen, —CF 3 , —OH, —O—(C 1 -C 3 )alkyl, —CO—(C 1 -C 3 )alkyl, —(C 1 -C 5 )alkyl-NRaRb, —NRaRb and —SO 2 NH 2 ; 
 with the proviso that R2 does not represent 2-(4-fluorophenyl)ethyl. 
 
     
     
         2 . A compound according to  claim 1  wherein R1 represents —(CH 2 ) 0-3 -(5-6)Hetcy, —(CH 2 ) 1-3 -(5-10)Hetar, —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl) or —(CH 2 ) 1-3 -(2-naphthyl), all of them optionally substituted. 
     
     
         3 . A compound according to  claim 1  wherein R2 represents —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl) or —(CH 2 ) 2 —CH(phenyl) 2 , all of them optionally substituted, with the proviso that R2 does not represent 2-(4-fluorophenyl)ethyl. 
     
     
         4 . A compound according to  claim 1  wherein R3 represents —(CH 2 ) 1-3 -(5-6)Hetar or —(CH 2 ) 2 -phenyl, both optionally substituted. 
     
     
         5 . A compound which is a drug conjugate comprising a radical of formula II 
       
         
           
           
               
               
           
         
       
       its stereoisomers and mixtures thereof and the pharmaceutically acceptable solvates and addition salts thereof, conjugated to a polyglutamic acid polymer, wherein R1, R2 and R3 have the meanings as defined in  claim 1  without the R2 proviso; each R4 independently represents a side chain from any of the 20 naturally occurring amino acids, and n is 0, 1, 2 or 3. 
     
     
         6 . A compound of formula III which is a drug conjugate according to  claim 2   
       
         
           
           
               
               
           
         
       
       wherein the proportion of y to x is 25-30% to 75-70% by weight. 
     
     
         7 . A compound according to  claim 5  wherein the polyglutamic acid is poly(L-glutamic acid); n represents 2 and R4 represents a glycine side chain. 
     
     
         8 . A method of treating or preventing diseases or conditions associated with the inhibition of apoptosis comprising administering a compound of formula I 
       
         
           
           
               
               
           
         
       
       its stereoisomers and mixtures thereof, its polymorphs and mixtures thereof, the pharmaceutically acceptable solvates and addition salts thereof, or compositions thereof wherein:
 R1 represents (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, —(CH 2 ) 1-3 —NHCO—(C 1 -C 3 )alkyl, —(CH 2 ) 1-3 —CONRaRb, —(CH 2 ) 0-3 -(3-6)Cy, —(CH 2 ) 0-3 -(5-6 Hetcy, —(CH 2 ) 1-3 -phenyl, —(C 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), —(CH 2 ) 1-3 -(5-10 Hetar, —(CH 2 ) 2 —CH(phenyl) 2 , —(CH 2 ) 2 —CH(phenyl)[(5-6)Hetar] or —(CH 2 ) 2 —CH[(5-6)Hetar] 2 , 
 R2 represents —(CH 2 ) 0-3 -(3-6)Cy, —(CH 2 ) 0-3 -(5-6)Hetcy, —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), —(CH 2 ) 1-3 -(5-10)Hetar, —(CH 2 ) 2 —CH(phenyl) 2 , —(CH 2 ) 2 —CH(phenyl)[(5-6)Hetar] or —(CH 2 ) 2 —CH[(5-6)Hetar] 2 ; 
 R3 represents —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), (CH 2 ) 1-3 -(2-naphthyl), or —(CH 2 ) 1-3 -(5-6)Hetar; 
 (C 1 -C 5 )alkyl and —(C 2 -C 5 )alkenyl may be optionally substituted with one or more substituents selected from —O—(C 1 -C 2 )alkyl, —S—(C 1 -C 2 )alkyl, —NH 2 , —NH—(C 1 -C 2 )alkyl and —N[(C 1 -C 2 )alkyl] 2 ; 
 (C 1 -C 3 )alkyl can be optionally substituted with one or more halogen atoms; 
 Ra and Rb independently represent —H or —(C 1 -C 3 )alkyl 
 (3-6)Cy represents a radical of a 3- to 6-membered partially unsaturated or saturated carbocyclic ring; 
 (5-6)Hetcy represents a C- or N-radical of a 5- or 6-membered, partially unsaturated or saturated carbocyclic ring containing from one or two heteroatoms independently selected from O, S and N; 
 Cy and Hetcy can be optionally substituted with one or more substituents selected from halogen, —CF 3  and —OH; 
 (5-6)Hetar and (5-10)Hetar represent a C- or N-radical of an aromatic 5- or 6-membered and 5- to 10-membered ring respectively; containing from one to four heteroatoms independently selected from O, S and N; 
 phenyl, 1-naphthyl, 2-naphthyl, (5-6)Hetar and (5-10)Hetar may be optionally substituted with one or more substituents selected from halogen, —CF 3 , —OH, —O—(C 1 -C 3 )alkyl, —CO—(C 1 -C 3 )alkyl, —(C 1 -C 5 )alkyl-NRaRb, —NRaRb and —SO 2 NH 2 ; 
 or a compound which is a drug conjugate comprising a radical of formula II 
 
       
         
           
           
               
               
           
         
       
       its stereoisomers and mixtures thereof, or the pharmaceutically acceptable solvates and addition salts thereof, conjugated to a polyglutamic acid polymer, wherein
 R1 represents (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, —(CH 2 ) 1-3 —NHCO—(C 1 -C 3 )alkyl, —(CH 2 ) 1-3 —CONRaRb, —(CH 2 ) 0-3 -(3-6)Cy, —C 2 ) 0-3 -(5-6)Hetcy, —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), —(CH 2 )-(5-10)Hetar, —(CH 2 ) 2 —CH(phenyl) 2 , —(CH 2 ) 2 —CH(phenyl)[(5-6)Hetar] or —(CH 2 ) 2 —CH[(5-6)Hetar] 2 ; 
 R2 represents —(CH 2 ) 0-3 -(3-6)Cy, —(CH 2 ) 0-3 -(5-6)Hetcy, —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), —(CH 2 ) 1-3 -(5-10)Hetar, —(CH 2 ) 2 —CH(phenyl) 2 , —(CH 2 ) 2 —CH(phenyl)[(5-6)Hetar] or —(CH 2 ) 2 —CH[(5-6)Hetar] 2 ; 
 R3 represents —(CH 2 ) 1-3 -phenyl, —(CH 2 ) 1-3 -(1-naphthyl), —(CH 2 ) 1-3 -(2-naphthyl), or —(CH 2 ) 1-3 -(5-6)Hetar; 
 (C 1 -C 5 )alkyl and —(C 2 -C 5 )alkenyl may be optionally substituted with one or more substituents selected from —O—(C 1 -C 2 )alkyl, —S—(C 1 -C 2 )alkyl, —NH 2 , —NH—(C 1 -C 2 )alkyl and —N[(C 1 -C 2 )alkyl] 2 ; 
 (C 1 -C 3 )alkyl can be optionally substituted with one or more halogen atoms; 
 Ra and Rb independently represent —H or —(C 1 -C 3 )alkyl 
 (3-6)Cy represents a radical of a 3- to 6-membered partially unsaturated or saturated carbocyclic ring; 
 (5-6)Hetcy represents a C- or N-radical of a 5- or 6-membered, partially unsaturated or saturated carbocyclic ring containing from one or two heteroatoms independently selected from O, S and N; 
 Cy and Hetcy can be optionally substituted with one or more substituents selected from halogen, —CF 3  and —OH; 
 (5-6)Hetar and (5-10)Hetar represent a C- or N-radical of an aromatic 5- or 6-membered and 5- to 10-membered ring respectively; containing from one to four heteroatoms independently selected from O, S and N; 
 phenyl, 1-naphthyl, 2-naphthyl, (5-6)Hetar and (5-10)Hetar may be optionally substituted with one or more substituents selected from halogen, —CF 3 , —OH, —O—(C 1 -C 3 )alkyl, —CO—(C 1 -C 3 )alkyl, —(C 1 -C 5 )alkyl-NRaRb, —NRaRb and —SO 2 NH 2 ; and 
 each R4 independently represents a side chain from any of the 20 naturally occurring amino acids, and n is 0, 1, 2 or 3. 
 
     
     
         9 . The method according to  claim 8  wherein the condition is selected from stroke, traumatisms, brain injury, spinal cord injury, meningitis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, multiple sclerosis, prion-related Diseases, myocardial ischaemia, as well as other acute or chronic cardiovascular diseases, organ transplantation, alcoholic related pathologies or treatment of allopecia. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . A composition which comprises an effective amount of a compound of formula I as defined in  claim 1 , a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutical acceptable excipients. 
     
     
         13 . A pharmaceutical composition according to  claim 12  in the form of nanospheres, microparticles and nanoparticles. 
     
     
         14 . A composition which comprises an effective amount of a compound as defined in  claim 5 , a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutical acceptable excipients.